A disalicylic acid-furanyl derivative inhibits ephrin binding to a subset of Eph receptors.
A disalicylic acid-furanyl derivative inhibits ephrin binding to a subset of Eph receptors.
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多叶酸 - 氟烷基衍生物抑制了Ephrin与EPH受体的一部分结合。
DOI：
10.1111/j.1747-0285.2011.01199.x
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发表时间：
2011-10
影响因子：
3
通讯作者：
Pasquale EB
中科院分区：
文献类型：
--
作者：
Noberini R;De SK;Zhang Z;Wu B;Raveendra-Panickar D;Chen V;Vazquez J;Qin H;Song J;Cosford ND;Pellecchia M;Pasquale EB
Eph受体酪氨酸激酶和ephrin配体控制许多生理和病理过程，干扰它们相互作用的分子是阐明其复杂生物学功能的有用探针。此外，靶向Eph受体可能使抑制癌症进展和病理性血管生成以及促进神经再生的新策略成为可能。由于我们先前的工作表明水杨酸基团在靶向Eph受体的拮抗性小分子中的重要性，我们筛选了一系列水杨酸衍生物以鉴定新型Eph受体拮抗剂。这鉴定了一种双水杨酸-呋喃基衍生物，其在ELISA测定中以3 μM的IC 50抑制肝配蛋白-A5与EphA 4的结合。这种化合物似乎与EphA 4的肝配蛋白结合口袋结合，也靶向其他几种Eph受体。此外，它抑制用ephrin刺激的细胞中的EphA 2和EphA 4酪氨酸磷酸化，同时不影响EphB 2的磷酸化，EphB 2不是靶受体。在内皮细胞中，双水杨酸-呋喃基衍生物抑制EphA 2响应于TNFα的磷酸化和基质胶上的毛细血管样管形成，这两种效应取决于EphA 2与内源性肝配蛋白-A1的相互作用。这些发现表明，水杨酸衍生物可用作设计新的Eph受体的小分子拮抗剂的起点。
Eph receptor tyrosine kinases and ephrin ligands control many physiological and pathological processes, and molecules interfering with their interaction are useful probes to elucidate their complex biological functions. Moreover, targeting Eph receptors might enable new strategies to inhibit cancer progression and pathological angiogenesis as well as promote nerve regeneration. Because our previous work suggested the importance of the salicylic acid group in antagonistic small molecules targeting Eph receptors, we screened a series of salicylic acid derivatives to identify novel Eph receptor antagonists. This identified a disalicylic acid-furanyl derivative that inhibits ephrin-A5 binding to EphA4 with an IC50 of 3 μM in ELISA assays. This compound, which appears to bind to the ephrin-binding pocket of EphA4, also targets several other Eph receptors. Furthermore, it inhibits EphA2 and EphA4 tyrosine phosphorylation in cells stimulated with ephrin while not affecting phosphorylation of EphB2, which is not a target receptor. In endothelial cells, the disalicylic acid-furanyl derivative inhibits EphA2 phosphorylation in response to TNFα and capillary-like tube formation on Matrigel, two effects that depend on EphA2 interaction with endogenous ephrin-A1. These findings suggest that salicylic acid derivatives could be used as starting points to design new small molecule antagonists of Eph receptors.
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影响因子：
3.4
作者：
Ehlken, Christoph;Martin, Gottfried;Agostini, Hansjuergen T.
通讯作者：
Agostini, Hansjuergen T.
影响因子：
3.6
作者：
Hess, AR;Seftor, EA;Hendrix, MJC
通讯作者：
Hendrix, MJC
影响因子：
3.4
作者：
Fabes, Jez;Anderson, Patrick;Bolsover, Stephen
通讯作者：
Bolsover, Stephen
影响因子：
2.5
作者：
Goldshmit, Yona;Galea, Mary P.;Turnley, Ann M.
通讯作者：
Turnley, Ann M.
影响因子：
8
作者：
Brantley, DM;Cheng, N;Chen, J
通讯作者：
Chen, J